Critical Reviews in Oncology/Hematology 59 (2006) 226–233
Pathological, biological and clinical characteristics, and surgical management, of elderly women with breast cancer Annamaria Molino a,∗ , Monica Giovannini a , Alessandra Auriemma a , Elena Fiorio a , Anna Mercanti a , Marta Mandar`a a , Alessia Caldara a , Rocco Micciolo b , Michele Pavarana a , Gian Luigi Cetto a a
Department of Medical Oncology, University of Verona, Verona, Italy b Institute of Statistics, University of Trento, Trento, Italy Accepted 20 January 2006
Contents 1. 2.
3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Pathological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Biological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Surgical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Statistical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Univariate analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Multivariate analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
226 227 227 227 227 227 228 228 229 230 230 231 231 232
Abstract For this retrospective study, we divided 3814 patients with invasive operable breast cancer into five groups based on their age at diagnosis. Univariate analysis showed that the elderly women had larger tumours with more axillary node involvement and lymphovascular invasion, more estrogen- and progesterone-positive tumours, lower grades and proliferative indices, and were less likely to be c-erbB2 positive. They were more likely to have been diagnosed in a symptomatic state and to have undergone mastectomy, and less likely to have undergone mammary reconstruction or axillary dissection, or to have a family history of breast cancer. The multinomial regression model showed that pT, pN, ER, PgR, the type of diagnosis, and a family history were independently associated with each other. The results of this study show that elderly women are more likely to have larger and more frequently N+ tumours, but these are biologically less aggressive and usually seem to receive less invasive surgical treatment. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Breast cancer; Biological/pathological/clinical characteristics; Surgical management; Elderly patients; Prognostic factors
1. Introduction ∗ Corresponding author at: Divisione Clinicizzata di Oncologia Medica, Ospedale Maggiore, Piazzale Stefani 1, 37124 Verona, Italy. Tel.: +39 045 8072342; fax: +39 045 8072141. E-mail address:
[email protected] (A. Molino).
1040-8428/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2006.01.007
Breast cancer is a major health problem throughout the world, and its incidence is increasing in many countries. Age is one of the major risk factors: approximately 50% of all new
A. Molino et al. / Critical Reviews in Oncology/Hematology 59 (2006) 226–233
breast cancers occur in women aged 65 years or more, who also experience the majority of breast cancer-related deaths [1]. The proportion of elderly subjects in the general population is increasing: the 65-year-old population in the United States accounted for 11.3% of the total population in 1980, and is estimated to reach 20.1% by 2030 [2]. Epidemiological data do not show that age itself plays a determinant role in the risk of developing cancer, but the process of aging can be considered a surrogate marker of prolonged carcinogen exposure [3]; however, the specific age incidence curve of some hormone-related neoplasms (including breast cancer) can only be explained on the basis of chronological or, rather, breast tissue age [4]. Given the current demographic trends, the number of elderly women diagnosed as having breast cancer is likely to increase substantially in the future: for example, it has been estimated that, assuming a constant incidence rate, there will be a 72% increase in the number of breast cancer diagnoses among elderly women in the US by 2025 [5]. If this projection is true, the magnitude of the increase will have profound implications for the delivery of medical care. Although relatively little is known about possible differences in the pathology and biology of breast cancer in older patients, it has been reported that advanced age is associated with favourable biological features and that elderly patients receive less aggressive and intensive treatment [6–11]. This difference in therapeutic approach can be explained on various grounds, including greater treatment toxicity in older patients with significant comorbid conditions [12], and the indolent nature and relatively slower growth of breast tumours in such patients [13,14]. The aim of this retrospective study was to verify the hypothesis that breast tumours in the elderly behave more favourably than those in younger women, and to confirm that age influences the surgical management of breast cancer patients. In order to do this, we reviewed the clinical, biological and pathological characteristics of a series of 3814 consecutive patients with operable breast cancer recruited in a single institution over a 10-year period.
2. Patients and methods This retrospective study involved 3814 women with previously untreated primary invasive breast cancer who underwent surgery at the University and Civic Hospitals of Verona between January 1992 and June 2002. All of the data were collected using the Breast Cancer Registry founded in Verona in 1992. The case series was consecutive with respect to the laboratory accrual of tumour material at the time of diagnosis. All of the patients had a histologically confirmed diagnosis of breast cancer, but we excluded those with a diagnosis of in situ ductal or lobular carcinomas, or breast sarcomas. All of the patients were assigned a pathological TNM stage
227
according to the UICC criteria. Immediately after surgery, the tumour specimens sampled by pathologists were used to make a histological diagnosis and for in vitro determinations. 2.1. Pathological features The pathological size (pT) and diameter of the tumours (in millimetres) were recorded, as was their grade (G), the number of pathologically positive axillary nodes (pN), and the presence of multifocal lesions and lymphovascular invasion. 2.2. Biological features Estrogen (ER) and progesteron receptor (PgR) status were determined by means of immunohistochemistry (ICH) as previously described in detail [15], with the tumours being considered ER or PgR positive if more than 10% of the cells were stained. Immunohistochemical staining for the replicative cell fraction was performed using the Ki-67 monoclonal antibody (Mab-DAKO-PC) as previously described [16]. The tumours were arbitrarily considered as having a high or low proliferative index if the percentage of Ki-67 positive cells was respectively more or less than 30%. C-erbB2 levels were determined by means of ICH using the DAKO-PC monoclonal antibody, and the tumours were considered positive if at least one cell was stained; FISH gene amplification results were not used because the method has only recently been introduced in our institute, and data are available for only a few patients. In the case of BCL2, only the cells that were completely and darkly stained at cytoplasmic level were regarded as positive; the cut-off value was set at 30% [17–19]. 2.3. Clinical features The clinical variables were the family history of breast cancer, classified as no family history, or a first- or seconddegree family history, and the type of disease presentation, with the patients being classified as symptomatic if they underwent mammography and ultrasonography because of a breast mass or discomfort, or asymptomatic if they underwent these examinations without any subjective symptoms. 2.4. Surgical management In terms of surgical management, we evaluated the type of local treatment (breast conservation surgery by means of a wide resection or quadrantectomy, or radical or modified mastectomy), axillary dissection, and whether breast reconstruction was performed. All of the patients who underwent conservative surgery received adjuvant radiation therapy on the remaining breast tissue; since 1999, all of the mastectomised patients with pT3-T4 tumours and/or more than four positive axillary nodes have received radiation therapy of the chest wall and homolateral supraclavicular region in order to
228
A. Molino et al. / Critical Reviews in Oncology/Hematology 59 (2006) 226–233
reduce the risk of local recurrence according to the St. Gallen Consensus Conference. Given the absence of a standard cut-off point, the patients were arbitrarily divided into five groups on the basis of their age at diagnosis (75 years) in order to identify any age-related differences in terms of the pathological, biological and clinical features of the breast cancers, and their surgical management. 2.5. Statistical methods The chi-squared test and multinomial logistic regression [20] were used to identify any age-related differences in the breast cancers and their surgical management. The pathological and clinical features of the tumours as a function of patient age were studied by evaluating the significance of the trend with age. Three different age-related patterns were investigated: (a) a linear trend: i.e. a progressive decrease (or increase) with age in the percentage of tumours with the considered feature; (b) a quadratic trend: i.e. the presence of higher (or lower) percentages of tumours with the considered feature in both the youngest and oldest patients; and (c) a discontinuous age-related pattern. A trend was considered linear when neither the quadratic or higher order trends were significant (p-values greater than 0.05); a trend was considered quadratic when the higher order trend was not significant (regardless of the p-value of the linear trend); finally a discontinuous age-related pattern was indicated by a significant higher order trend (regardless of the p-values of the linear and quadratic trends). Tumour diameter was classified as pT1 (5 cm) or pT4 (skin or chest wall involvement); node status as negative, 1–3, 4–10 or >10 positive nodes; grading as G1, G2 or G3; multifocality as yes or no; and lymphovascular invasion as yes or no. The biolog-
ical classes were: ER and PgR negative or positive (≤ or >10% stained cells); Ki-67 ≤30% and >30% stained cells; c-erbB2 negative or positive; and BCL2 negative or positive. The clinical classes were disease presentation (symptomatic or asymptomatic), and family history (no family history, affected first-degree or second-degree relatives). The surgical management classes were local treatment (breast conservation surgery or mastectomy), axillary dissection (yes or no), and breast reconstruction (yes or no). STATA statistical software version 7.0 (Stata Corporation, College Station, Tex, 2003) was used for the univariate and multivariate analyses (using the mlogit command); p-values of less than 0.05 were considered significant. Interaction tests were performed to investigate the homogeneity of effects across the age categories, and the likelihood ratio test was used to evaluate the significance of the interaction terms and the trend with age.
3. Results Five hundred and forty-three of the 3814 patients were aged 75 years; 37% of the patients were therefore considered elderly (aged 65 years or more). Tables 1–4 summarise the characteristics of the patients in terms of the categorical variables and by age at diagnosis, and the results of the chi-square test. About 5% of the patients were pT4 , but were included in the analysis because they were operable at the time of diagnosis and only pathological examination revealed microscopic skin or chest wall involvement. As information concerning BCL2, multifocal lesions and lymphovascular invasion was only available for respectively 702, 627 and 1381
Table 1 Pathological characteristics of breast cancer patients
